转移性结肠癌的一种新的治疗模式PPT课件.ppt

AnewtreatmentparadigmformCRC Heinz JosefLenzProfessorofMedicineAssociateDirector ClinicalResearchUSCNorrisComprehensiveCancerCenterLosAngeles CA Anti EGFRantibodiesinmCRC Comparisonofcetuximabandbevacizumab Bleedingpossible wound healingcomplications Nocomplications Perioperative Hypertension thromboembolicevents Acne likeskinrash Specificsideeffect RRwithFOLFOX RRwithFOLFIRI Firstline Second thirdline Registered Yes Single agentactivity VEGFprotein EGFreceptor Antibody Bevacizumab Cetuximab Characteristic PhaseIIICRYSTALstudy Studydesign Stratificationfactors RegionECOGperformancestatusPopulations Randomizedpatients n 1217 Safetypopulation n 1202 ITTpopulation n 1198 FOLFIRIIrinotecan 180mg m2 5 FU 400mg m2bolus 2400mg m2as46 hcontinuousinfusion LV every2weeks ERBITUX FOLFIRIERBITUX IV400mg m2onday1 then250mg m2weekly irinotecan 180mg m2 5 FU 400mg m2bolus 2400mg m2as46 hcontinuousinfusion LV every2weeks R EGFR expressingmCRC VanCutsemE etal ASCO2007 AbstractNo 4000 Studyendpoints PrimaryendpointPFStime asassessedbyblindedindependentreview SecondaryendpointsORR independentlyreviewed DCR CR PR SD OSQualityoflife EORTCQLQ C30 Safety VanCutsemE etal ECCO2007 AbstractNo 3001 Primaryendpoint PFS ITTpopulation PFSestimate VanCutsemE etal ASCO2007 AbstractNo 4000 PFStime months 1 yearPFSrate 23 vs34 PFSITT HR 0 85 p 0 048mPFSERBITUX FOLFIRI 8 9monthsmPFSFOLFIRI 8 0months Independentassessmentofresponse VanCutsemE etal ECCO2007 AbstractNo 3001 39 47 Responserate p 0 0038a aCochran Mantel Haenszeltest KRASanalysis Objectiveandmethodology ToretrospectivelyinvestigatetheimpactoftheKRASmutationstatusoftumorsonPFSandRRinthefirst linetreatmentofmCRCwithFOLFIRI ERBITUXEfficacyanalysesrepeatedonKRASevaluablepopulationGenomicDNAisolatedfromarchivedtumormaterialParaffin embedded formalin fixedtissueKRASmutationstatusofcodons12 13determinedusingquantitativePCR basedassay VanCutsemE etal JClinOncol2008 26 Suppl abstract2 KRASevaluablepopulation 587subjectsanalysedforKRASmutationstatus 540 45 subjects KRASevaluablepopulation 348 64 4 KRASwild type 192 35 6 KRASmutant 171subjectswithevents 49 1 GroupA 105 54 7 GroupB 87 45 3 101subjectswithevents 52 6 1198subjects ITT GroupA 172 49 4 GroupB 176 50 6 FOLFIRI ERBITUX FOLFIRI VanCutsemE etal JClinOncol2008 26 Suppl abstract2 PatientdemographicsatbaselineaccordingtoKRASstatus VanCutsemE etal JClinOncol2008 26 Suppl abstract2 ITTandKRASevaluablepopulation Comparability ITTpopulation n 1198 HR 0 85MedianPFS ERBITUX FOLFIRI8 9monthsvsFOLFIRI8 0months KRASpopulation n 540 HR 0 82MedianPFS ERBITUX FOLFIRI9 2monthsvsFOLFIRI8 7months 1 0 PFSestimate Time Months 0 5 0 4 0 3 0 2 0 1 0 6 0 7 0 8 0 9 0 0 8 0 2 4 6 10 12 14 16 18 20 0 5 1 0 0 4 0 3 0 2 0 1 0 6 0 7 0 9 0 0 8 0 2 4 6 10 12 14 16 18 20 0 8 Time Months PFSestimate ERBITUX FOLFIRI FOLFIRI VanCutsemE etal JClinOncol2008 26 Suppl abstract2 First lineERBITUX FOLFIRI CorrelationofKRASstatuswithefficacy First linetreatment ERBITUX 6weeksmonotherapy followedbyERBITUX FOLFIRI n 52 TaberneroJetal ASCOGI2008 RelatingKRASstatustoefficacyPrimaryendpoint PFS KRASwild type VanCutsemE etal JClinOncol2008 26 Suppl abstract2 RelatingKRASstatustoefficacyPrimaryendpoint PFS KRASmutant VanCutsemE etal JClinOncol2008 26 Suppl abstract2 RelatingKRASstatustoefficacy PFS ERBITUX FOLFIRIHR 0 63 p 0 007 MedianPFS Wild type n 172 9 9monthsvsmutant n 105 7 6months FOLFIRIHR 0 97 p 0 87 MedianPFS Wild type n 176 8 7monthsvsmutant n 87 8 1months 0 5 1 0 0 4 0 3 0 2 0 1 0 0 0 6 0 7 0 8 0 9 8 0 2 4 6 10 16 PFSestimate Time months 12 14 0 5 1 0 0 4 0 3 0 2 0 1 0 0 0 6 0 7 0 8 0 9 Time months FOLFIRIwild type FOLFIRImutant 8 0 2 4 6 10 16 12 14 PFSestimate VanCutsemE etal JClinOncol2008 26 Suppl abstract2 RelatingKRASstatustoefficacySecondaryendpoint Response p 0 0025a FOLFIRI ERBITUX FOLFIRI aCochran Mantel Haenszel CMH test KRASwild type n 348 KRASmutant n 192 p 0 46a FOLFIRI ERBITUX FOLFIRI VanCutsemE etal JClinOncol2008 26 Suppl abstract2 RelatingKRASstatustooutcome Mostcommongrade3 4adverseevents aTherewasnograde4acne likerash VanCutsemE etal JClinOncol2008 26 Suppl abstract2 Conclusions CRYSTALstudy AddingERBITUXtoFOLFIRIinmCRCleadstoasignificantincreaseinPFS HR 0 85 p 0 048 ThebenefitofERBITUX FOLFIRIisgreaterinpatientswithKRASwild typetumors PFS HR 0 68 p 0 017 Responserate59 vs43 p 0 0025 Thegrade3 4adverse eventprofilewassimilarintheKRASwild typeandmutantpopulations OPUS Studydesign PrimaryendpointOverallconfirmedresponserate asassessedbyindependentreview SecondaryendpointsPFStimeOStimeRateofcurativesurgeryformetastasesSafety ERBITUX FOLFOX4a400mg m2initialIVinfusion day1 then250mg m2weekly oxaliplatin85mg m2 5 FU LVevery2weeks FOLFOX4aOxaliplatin85mg m2 5 FU LVevery2weeks EGFR detectablemCRC R Stratificationby ECOGPS0 1 2 BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 aTreatmentuntilprogression symptomaticdeteriorationorunacceptabletoxicity PhaseIIOPUStrial KRASanalysis ObjectiveToretrospectivelyinvestigatetheimpactoftheKRASmutationstatusoftumorsontheresponserateandPFSinthefirst linetreatmentofmCRCwithFOLFOX ERBITUX BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 KRASevaluablepopulation 233 69 subjects KRASevaluablepopulation 134 58 KRASwild type 99 42 KRASmutant GroupA 52 53 GroupB 47 47 337subjects ITT GroupA 61 46 GroupB 73 54 FOLFOX ERBITUX FOLFOX BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 Patientdemographicsatbaseline BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 KRASwild type n 134 58 KRASmutant n 99 42 p 0 011 p 0 16 RoleofKRASstatusinresponserate BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 37 61 49 33 RelatingKRASstatustoefficacySecondaryendpoint PFS KRASwild type 0 5 1 0 0 4 0 3 0 2 0 1 0 0 0 6 0 7 0 8 0 9 8 0 2 4 6 10 12 Months KRASwild type HR 0 57 p 0 016mPFSERBITUX FOLFOX 7 7monthsmPFSFOLFOX 7 2months Progression freesurvivalestimate BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 RelatingKRASstatustoefficacySecondaryendpoint PFS KRASmutant KRASmutantHR 1 83 p 0 0192mPFSERBITUX FOLFOX 5 5monthsmPFSFOLFOX 8 6months 0 5 1 0 0 4 0 3 0 2 0 1 0 0 0 6 0 7 0 8 0 9 8 0 2 4 6 10 12 Months Progression freesurvivalestimate BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 RelatingKRASstatustoefficacy Progression freesurvival 0 5 1 0 0 4 0 3 0 2 0 1 0 0 0 6 0 7 0 8 0 9 8 0 2 4 6 10 12 PFSestimate Time months 0 5 1 0 0 4 0 3 0 2 0 1 0 0 0 6 0 7 0 8 0 9 8 0 2 4 6 10 12 Time months ERBITUX FOLFOXHR 0 45 p 0 0009mPFSCet FOLFOXwild type n 61 7 7monthsmPFSCet FOLFOXmutant n 52 5 5months FOLFOXHR 1 40 p 0 1655mPFSFOLFOXwild type n 73 7 2monthsmPFSFOLFOXmutant n 47 8 6months PFSestimate BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 Mostcommongrade3 4AEs aTherewasnograde4acne likerash BokemeyerC etal JClinOncol2008 26 Suppl abstract4000 Conclusions OPUSstudy TheadditionofERBITUXtoFOLFOXincreasedtheresponserateby10 46 vs36 InpatientswithKRASwild typetumors additionofERBITUXtoFOLFOXresultedinasignificantandrelevantimprovementin Responserate 61 vs37 p 0 011 PFS HR 0 57 p 0 016 1 VanCutsemE etal JClinOncol2008 26 AbstractNo 2 2 BokemeyerC etal JClinOncol2008 26 AbstractNo 4000 ERBITUX CTinKRASwild type Consistentresults Responserate 59 37 0 10 20 30 40 50 60 70 CRYSTAL1 n 348 OPUS2 n 134 43 61 FOLFIRI FOLFOX ERBITUX FOLFIRI ERBITUX FOLF0X CRYSTAL KRASwild type HR 0 68 p 0 017 32 riskreductionforprogression OPUS KRASwild type HR 0 57 p 0 016 43 riskreductionforprogression 0 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 1 0 0 2 4 6 8 10 12 14 16 18 Time months PFSestimate 0 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 1 0 0 2 4 6 8 10 12 Time months PFSestimate ERBITUXinpretreatedmCRC EvidenceofcorrelationbetweenKRASwild typeandEGFRinhibitorefficacyinchemorefractoryCRC Response NCICCTGCO 17KarapetisC etal WCGIC2008June2810 45SessionXVII RoleofKRASmutationsinpredictingresponse progression freesurvivalandoverallsurvivalinirinotecan refractorypatientstreatedwithcetuximabplusirinotecanforametastaticcolorectalcancer Analysisof281individualdatafrompublishedseriesAbstractO 018 WorldCongressGICancer Barcelona2008DiFioreF 1 VanCutsemE 1 Laurent PuigP 2 SienaS 3 FrattiniM 4 DeRoockW 1 LievreA 2 Sartore BianchiA 3 BardelliA 5 TejparS 1 1 DigestiveOncologyUnit UniversityHospitalGasthuisberg Leuven Belgium 2 InstitutNationaldelaSant etdelaRechercheM dicaleU775 Universit Paris Descartes Paris France 3 DivisioneOncologiaMedicaFalck OspedaleNiguardaCa Granda Milan Italy 4 InstituteOfPathology Locarno Switzerland 5 LaboratoryofMolecularGeneticsInstituteforCancerResearchandTreatment UniversityofTorinoMedicalSchool Torino Italy Responsetocetuximab IrinotecanaccordingtoKRASstatus n 281 DiFioreF VanCutsemEetal WCGICBarcelona AnnOncol 2008abstractO 018 MetaanalysisinchemorefractoryCRC 6 MetaanalysisinchemorefractoryCRC PFSaccordingtoKRASstatus DiFioreF VanCutsemEetal WCGICBarcelona AnnOncol 2008abstractO 018 OSaccordingtoKRASstatus MetaanalysisinchemorefractoryCRC DiFioreF VanCutsemEetal WCGICBarcelona AnnOncol 2008abstractO 018 OverallsurvivalaccordingtoKRASmutationandskintoxicity Time months 1 00 0 75 0 50 0 25 0 00 0 10 20 30 p 0 0008 15 6months 95 CI 10 9 22 10 7months 95 CI 8 3 16 3 5 6months 95 CI 2 8 10 6 Survivalprobability 2goodprognosticfactors wild typeandgrade2 3skintoxicity 0goodprognosticfactors KRASmutantandgrade0 1skintoxicity 1goodprognosticfactor wild typeorgrade2 3skintoxicity Li vreA etal JClinOncol2008 NCICCO 17 randomizedphaseIIItrial EGFRtestingbyIHC DiseaseprogressionorUnacceptabletoxicity Stratification CenterECOGPS 0or1vs2 REGISTER RANDOMIZE 1 1 ERBITUX BSC BSCalone Failedorintoleranttoallrecommendedtherapies JonkerD etal NEnglJMed2008 ERBITUX BSC CENSORED BSC CENSORED Subjectsatrisk ERBITUX BSC 287 217 136 78 37 14 4 0 0 0 BSC 285 197 85 44 26 12 8 2 1 0 Proportionalive 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 1 0 Months 0 3 6 9 12 15 18 21 24 27 HR0 77 95 CI 0 64 0 92 Stratifiedlog rankp 0 0046 JonkerD etal NEnglJMed2008 NCICCTGCO 17 OverallSurvival ERBITUX BSC CENSORED BSC CENSORED Proportionprogression free 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 1 0 Months 0 3 6 9 12 15 HR0 68 95 CI 0 57 0 80 Stratifiedlog rankp 0 0001 JonkerD etal NEnglJMed2008 NCICCTGCO 17 ProgressionFreeSurvival NCICCTGCO 17K RasAnalysis GenomicDNAextractedfromFFPETslidesorsectionsAssessedbybidirectionalsequencingforcodon12 13mutationsNodifferencebetweenK rasmutatedandWTpatientsre demographics previoustreatmentorothervariables N 572randomized ITTsubset N 394 K rasassessedsubset 69 N 164 42 mutant N 230 58 wild type KarapetisCetal WCGICBarcelona 2008 ComparisonofITTandK rasassessedsubsets betweenmutatedandwild typeK RASgroupsfromchi squaretestforcategoricalvariablesandt testforcontinuousvariables KarapetisCetal WCGICBarcelona 2008 NCICCTGC0 17 Primaryendpointoverallsurvival Totalstudypopulation ITTanalysis K rasassessedsubset KarapetisCetal WCGICBarcelona 2008 NCICCTGC0 17 PFSintheMutantK rasSubgroup HR0 9995 CI 0 73 1 35 Logrankp value 0 96 KarapetisCetal WCGICBarcelona 2008 NCICCTGC0 17 PFSintheK rasWild TypePatients HR0 4095 CI 0 30 0 54 Logrankp value 0 0001 KarapetisCetal WCGICBarcelona 2008 NCICCTGC0 17 OverallsurvivalinK rasMutantpatients HR0 9895 CI 0 70 1 37 Logrankp value 0 89 KarapetisCetal WCGICBarcelona 2008 NCICCTGC0 17 OverallsurvivalinK rasWild Typepatients HR0 5595 CI 0 41 0 74 Logrankp value 0 0001 KarapetisCetal WCGICBarcelona 2008 NCICCTGC0 17 OverallSurvivalbyK rasStatusinBSCARM HR1 0195 CI 0 74 1 37 Logrankp value 0 97 KarapetisCetal WCGICBarcelona 2008 NCICCTGC0 17 OverallSurvivalbyK rasStatusinBSCARM HR1 0195 CI 0 74 1 37 Logrankp value 0 97 NOPROGNOSTICIMPACTOFK rasSTATUS KarapetisCetal WCGICBarcelona 2008 Conclusions pretreatedmCRC InpretreatedpatientswithmCRC ERBITUXshowssignificantlyincreasedsurvivalbenefitaswellasaPFSbenefitinpatientswithKRASwildtypetumorsErbituxincombinationwithirinotecani